Rare earth-doped nanomaterials are known as upconverting nanoparticles (UCNPs) convert low-energy near-infrared light into high-energy visible/ultraviolet light emissions. The anti-Stokes luminescence characteristics of these nanoparticles create special benefits for biomedical applications. Near-infrared light achieves deep tissue penetration while minimizing tissue damage and avoiding biological autofluorescence interference which leads to significantly better imaging sensitivity. UCNPs today serve important functions in bioimaging applications as well as cancer diagnosis and treatment through photothermal and photodynamic therapy combined with drug delivery systems and nanoscale temperature measurements. The promising applications of these materials require thorough safety assessments to understand their potential toxicity and long-term biosafety effects including rare earth element release and nanosize-induced outcomes.
Upconverting Nanoparticles Products List
Potential Toxicity Mechanisms of Upconverting Nanoparticles
Cytotoxicity of lanthanide metal ions released: The degradation of nanoparticles or the shedding of surface ligands can cause doped lanthanide metals like Yb³⁺ and Er³⁺ to release free ions which disrupt cell metabolism. Uncoated Er³⁺ ions binding to mitochondrial membranes cause membrane potential reduction which disrupts ATP synthesis and generates oxidative stress. Research findings demonstrate that exposure to Yb³⁺ activates apoptosis pathways within cells and causes DNA damage.Nano-sized biological barrier penetration: The nanoscale size (<100 nm) makes it easy to penetrate the blood-brain barrier and the placental barrier, and accumulate in the reticuloendothelial system organs such as the liver and spleen for a long time. Animal experiments have shown that the half-life of unmodified UCNPs in the liver can reach more than 30 days, which may induce hepatocyte vacuolation or spleen fibrosis. In addition, particles with a particle size of less than 10 nm can pass through glomerular filtration, but the surface charge and hydrophilicity may affect their excretion efficiency.
Nonspecific interactions caused by high surface activity: The high surface-to-volume ratio enhances the adsorption capacity with biological molecules. For example, the exposed hydrophobic surface is prone to hydrophobic interaction with the cell membrane phospholipid bilayer, destroying membrane fluidity and even causing membrane perforation. In addition, the Lewis acid sites on the surface of UCNPs (such as Y³⁺) can bind to the DNA phosphate backbone to interfere with the replication or transcription process.
Immunogenicity and oxidative damage: The "protein corona" formed by plasma proteins adsorbed on the hydrophobic surface may activate the complement system. For example, the release of C3a and C5a can trigger allergic reactions. Unmodified UCNPs surface defects (such as oxygen vacancies) can also catalyze the Fenton reaction, continuously produce reactive oxygen species (ROS), and lead to lipid peroxidation and mitochondrial DNA mutations.
Safety Assessment Strategy and Latest Research Progress
In vitro and in vivo comprehensive evaluation system
Toxicity is evaluated by multiple parameters (such as mitochondrial membrane potential, ROS level, cell cycle), and the sensitivity is more than 10 times higher than that of the traditional MTT method. The 28-day experiment of polyacrylic acid (PAA)-coated UCNPs in mice showed that 99% of the particles were excreted through glomerular filtration, and there was no abnormality in liver tissue pathology.
Dual protection of core-shell structure
The NaYF₄ shell can reduce the Yb³⁺ leakage rate to 0.03 μg/mL, while improving the luminescence efficiency (such as the green light intensity of NaYF₄:Yb/Er@NaGdF₄ is enhanced 50 times).
The shell doped with sensitizer Yb³⁺ (such as NaYF₄:Yb@NaYF₄) can increase the energy transfer efficiency to 80%, reduce the core dopant concentration to reduce toxicity.
Directed optimization of polymer coating
PEG modification makes the hemolysis rate of UCNPs <5%, reduces the risk of complement activation to the negative control level, and extends the circulation half-life to 12 hours.
Chitosan-coated UCNPs reduce protein adsorption through electrostatic repulsion, reducing the macrophage uptake rate by 70%.
Low toxicity cases and degradation pathways
The cell survival rate of polyacrylamide-modified UCNPs in in vitro experiments was >90% (72 hours), and in vivo degradation experiments showed that they were completely decomposed into fragments <5 nm within 28 days and excreted through the bile-feces pathway. In addition, mesoporous silica-coated UCNPs can achieve targeted release and metabolism through pH-responsive degradation (microacidic environment of tumors).
Safety Practices in Medical Applications
Bioimaging: Near-infrared excitation (980 nm) significantly increases the imaging depth to 10-15 mm subcutaneously by reducing tissue autofluorescence and scattering effects, which is particularly suitable for in vivo visualization monitoring of deep solid tumors (such as pancreatic cancer). The core-shell structure design (such as NaYF4 inert shell) can enhance the luminescence efficiency by more than 10 times, while reducing the risk of rare earth ion leakage. Modification with targeted ligands (such as folic acid and hyaluronic acid) can increase the tumor-specific uptake rate by 3-5 times, and reduce the capture of the reticuloendothelial system through polyethylene glycol (PEG) surface functionalization, extending the blood circulation half-life to more than 12 hours.
Integrated cancer diagnosis and treatment: UCNPs can convert 808 nm excitation light into 660 nm visible light through IR-806 dye sensitization, activate photosensitizers (such as Ce6, ZnPc) to produce singlet oxygen (1O2), and the photothermal conversion efficiency mediated by gold nanoshells reaches 70.7°C, realizing the dual mechanism of tumor ablation and vascular embolization. The Nd³⁺ doping system can realize real-time temperature feedback during treatment, improve the local temperature control accuracy to ±0.5°C, and avoid thermal damage to surrounding tissues.
UCNPs coated with mesoporous silica shells (pore size 2-3 nm) release doxorubicin through pH response (tumor microenvironment trigger) or 980 nm light control, with a release efficiency of 80% within 48 hours under acidic conditions, which is 60% lower than the systemic toxicity of traditional chemotherapy. The temperature-sensitive liposome composite system can quickly release drugs when the photothermal temperature rises to 42°C, realizing dual temporal and spatial regulation.
Nanoscale temperature measurement: Based on the temperature dependence of the fluorescence intensity ratio (FIR) of the ²H11/2 and ⁴S3/2 energy levels of Er³⁺, UCNPs can complete real-time temperature measurement in the range of -100°C to 500°C within 0.1 seconds, with a spatial resolution of 50 nm, which is suitable for chip hot spot positioning or tumor ablation boundary monitoring. Multi-parameter temperature-oxygen concentration synchronous sensing can be achieved through Tm³⁺ doping, providing multi-dimensional information for complex biological environments.
How to Choose Safe Upconverting Nanoparticles?
Prefer core-shell structures (such as NaYF₄@NaYF₄) or polyelectrolyte multilayer coated products, whose rare earth ion leakage rate is less than 0.1 ppm/month. The MTT experimental data (IC50>200 μg/mL) and 28-day subacute toxicity report (liver and kidney function index fluctuations <10%) provided by the supplier need to be verified.
Future Challenges and Research Directions
High-throughput screening platform: Use machine learning to optimize the Er³⁺/Tm³⁺ doping ratio (error <0.1 at.%) and predict the Pareto frontier of quantum yield and cytotoxicity.
Integrated diagnosis, treatment and monitoring: Probes based on the FRET mechanism can simultaneously monitor drug release (rhodamine B fluorescence recovery) and reactive oxygen levels (DCFH-DA oxidation) to achieve closed-loop regulation of therapeutic doses. CRISPR-Cas9 functionalized system can trigger gene editing through NIR for drug resistance reversal.
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